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TherapeuTics for The clinician
A Multicenter, Double-blind Study
to Evaluate the Efficacy and Safety of
2 Treatments in Participants With
Mild to Moderate Acne VulgarisZoe Diana Draelos, MD; Alan R. Shalita, MD; Diane Thiboutot, MD; Christian Oresajo, PhD;
Margarita Yatskayer; Susanna Raab
Acne treatment regimens have changed due to the peroxide (BPO) generally are regarded as safe and
recent over-the-counter (OTC) switch of all pre-
effective,1 which led to the movement from the
scription benzoyl peroxide (BPO) topical prepara-
prescription realm to the over-the-counter (OTC)
tions. The elimination of prescription single-agent market. The movement has increased the need for BPO products means that dermatologists must quality OTC BPO preparations to use as sole therapy select from a variety of OTC formulations to utilize in individuals with mild acne and in combination the time-tested efficacy of BPO in the treatment with prescription therapy in individuals with mild to of mild to moderate acne. Our research compared moderate acne. Most of the BPO preparations previ-the efficacy and safety of an OTC BPO 5.5% ously sold in the OTC market were based on the acne
Do Not Copyformulation with lipohydroxy acid and tretinoin monograph,1 but efficacy testing was not commonly cream 0.025% with prescription clindamycin 1%– performed. The preparations were assumed to be effi-BPO 5% gel and tretinoin cream 0.025%. Parity cacious based on the active BPO ingredient, which was demonstrated between the 2 treatment regi-
plays an important role in the treatment of acne.
mens at 12 weeks.
The most effective and most commonly used
active ingredient in OTC acne preparations is
BPO. Twenty-three percent of acne patients aged
he paradigm for acne treatment has changed 13 to 27 years have used an OTC BPO product.2
since the US Food and Drug Administration Benzoyl peroxide is a member of the organic perox-
determined that preparations with 10% benzoyl ide family consisting of 2 benzoyl groups joined by a
peroxide group. It has many properties pertinent to
Dr. Draelos is from the Department of Dermatology, Duke University
acne including antibacterial, anti-inflammatory, and
School of Medicine, Durham, North Carolina. Dr. Shalita is from the Department of Dermatology, State University of New York (SUNY),
comedolytic effects.3 When BPO touches the skin, it
Brooklyn. Dr. Thiboutot is from the Department of Dermatology,
breaks down into benzoic acid and oxygen, neither
Pennsylvania State University College of Medicine, Hershey.
of which is problematic. It has antimicrobial proper-
Dr. Oresajo, Ms. Yatskayer, and Ms. Raab are from L'Oréal USA, Inc,
ties against Propionibacterium acnes as demonstrated
Clark, New Jersey.
by a log10 2 decrease in P acnes concentration follow-
This study was sponsored by an unrestricted educational grant from La Roche-Posay Laboratoire Dermatologique. Dr. Draelos
ing 2 days of topical BPO 5% application.4 However,
received an educational grant from L'Oréal USA, Inc, and
unlike topical antibiotics, BPO does not induce
La Roche-Posay Laboratoire Dermatologique. Drs. Shalita and
resistant organisms.5 Even a BPO cleanser can sup-
Thiboutot are investigators for La Roche-Posay Laboratoire
press the development of resistant organisms.6
Dermatologique. Dr. Oresajo, Ms. Yatskayer, and Ms. Raab are
Benzoyl peroxide also acts as an anti-inflammatory
employees of L'Oréal USA, Inc. Correspondence: Zoe Diana Draelos, MD, 2444 N Main St,
agent by reducing oxygen radicals. Furthermore,
High Point, NC 27262 (zdraelos@northstate.net).
its ability to reduce the P acnes population also
VOLUME 89, JUNE 2012 287
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Therapeutics for the Clinician
reduces the activation of toll-like receptor 2 on the were masked to conceal their identity from both
surface of monocytes, leading to reduced secretion the participants and the investigators. Following
of proinflammatory cytokines such as tumor necrosis 12 weeks of product application, participants were
factor , IL-1, and IL-8.7 This anti-inflammatory asked to discontinue their acne treatment and enter
effect is perceived by the consumer as reduced red- a 4-week no-treatment phase known as a regression
ness and pain.
phase to determine the degree of acne relapse.
Benzoyl peroxide is capable of producing a 10%
Assessments—A variety of assessments were made
reduction of comedones in clinical trials.4 Higher- at baseline and weeks 2, 4, 8, and 12, with the regres-
concentration BPO preparations were originally sion phase assessment at week 16 in all enrolled
thought to provide superior antiacne effects; how- study participants. The 3 board-certified investiga-
ever, it now appears that even BPO 2.5% is effective tors were asked to blindly assess the participants
in improving acne.8
for tolerability (ie, erythema, edema, dryness, peel-
Current trends in BPO formulations have ing) on a 4-point ordinal scale (0none; 1mild;
focused on the use of less irritating hydrogel for- 2moderate; 3severe). In addition, lesion counts
mulations and smaller particle size BPO.9 Raw BPO were performed of the entire face including the nose
is a large particulate that is not water soluble. The for open comedones, closed comedones, papules, pus-
bulk of BPO in most formulations remains on the tules, noninflammatory lesions, inflammatory lesions,
surface of the stratum corneum. It is only the dis- and total lesions. The investigators also assessed the
solved BPO that reaches target areas in the skin and facial skin for skin tone (clarity), skin smoothness,
follicle where it is active in killing P acnes. Smaller skin brightness, appearance of pores, overall appear-
particle size allows better skin coverage with less ance, and global acne assessment on a 10-point visual
irritation, as it affords the opportunity to reduce analog scale with 0 indicating a favorable rating
the concentration of BPO. Careful creative formu- and 9 indicating an unfavorable rating. Participant
lation can minimize tolerability issues with OTC irritation assessments (stinging, tingling, itching,
BPO formulations.
burning) also were captured on a 4-point ordinal
We conducted a 12-week, multicenter, double- scale (0none; 1mild; 2moderate; 3severe)
blind study to compare the efficacy and safety of and standardized facial photography was conducted
2 acne regimen treatments (randomized in a with a 3-point head restraint of the front, right,
1:1 ratio) in patients with mild to moderate and left face to document the presence of partici-
acne. One treatment regimen included an pants at the research center. The photographs were
OTC formulation containing BPO 5.5% with not used for any efficacy assessments, as images can-
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lipohydroxy acid applied twice daily and treti- not duplicate the accuracy of real-time acne counts.
noin cream 0.025% applied at bedtime. The
Statistical Analysis—Data obtained from
other treatment regimen consisted of pre- the efficacy and tolerability evaluations were col-
scription clindamycin 1%–BPO 5% gel applied lected from all of the testing centers and statistically
twice daily and tretinoin cream 0.025% applied compared between baseline and weeks 2, 4, 8, 12,
and/or 16 using paired t tests or Wilcoxon signed
rank tests. Changes from baseline were considered
significant at .05. Mean percentage change from
Study Design and Treatment—Sixty-six participants baseline was reported for all attributes. Paired t tests
aged 18 to 50 years were enrolled in this multicenter, or Wilcoxon signed rank tests were applied to deter-
double-blind, institutional review board–approved, mine the differences between the 2 treatments.
12-week study. There were 3 research sites:
Dermatology Consulting Services, High Point, Results
North Carolina; State University of New York, Sixty-six participants were randomized and 60 par-
Brooklyn; and Pennsylvania State University ticipants completed the trial. Of the 60 partici-
College of Medicine, Hershey. Participants were pants, 26 received treatment A and generic tretinoin
randomized to treatment A or treatment B in a cream 0.025% and 34 received treatment B and
1:1 ratio. Treatment A consisted of an OTC generic tretinoin cream 0.025%. The study popu-
BPO 5.5% preparation with lipohydroxy acid lation was comprised of all ethnicities (32 white;
applied twice daily and tretinoin cream 0.025% 6 Hispanic; 2 Asian; 26 black); there were 54 female
applied at bedtime. Treatment B consisted of the participants and 12 male participants enrolled. Fol-
commonly prescribed clindamycin 1%–BPO 5% gel lowing the 12-week active treatment period, treat-
(BenzaClin) applied twice daily and tretinoin ment was discontinued. Participants refrained from
cream 0.025% applied at bedtime. Product labels other acne treatments and were reexamined after the
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Therapeutics for the Clinician
Table 1. Mean Scores on the Visual Analog Scale for Clinical Grading
for Efficacy ParametersaParameterb
Skin tone (clarity)
Appearance of pores Treatment A
Overall appearance
aTreatment A consisted of benzoyl peroxide 5.5% with lipohydroxy acid applied twice daily and tretinoin cream 0.025% applied at bedtime. Treatment B consisted of clindamycin 1%–benzoyl peroxide 5% gel applied twice daily and tretinoin cream 0.025% applied at bedtime.bRated using the visual analog scale with 0 indicating a favorable rating and 9 indicating an unfavorable rating.
4-week regression phase to determine how long the a statistically significant reduction in noninflamma-
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acne was controlled following cessation of treatment. tory and inflammatory lesion counts at treatment
A total of 57 participants completed the regression weeks 4, 8, and 12, and during the regression phase
phase. The study was initiated in September 2010 and at week 16 as compared with baseline (P.05).
was completed in August 2011.
Treatment B showed a statistically significant reduc-
Efficacy—The mean ordinal scores for the tion in open comedones at week 2 (P.05) that was
investigator efficacy assessment are summarized in not observed with treatment A; however, treatment A
Table 1. There was statistically significant improve- showed a statistically significant reduction in pus-
ment compared with baseline in all scores for both acne tules at week 2 (P.05) that was not seen with
treatment regimens at weeks 4, 8, and 12 (P.05). treatment B. Again, parity was established by the
Statistically significant improvement was main- 2 treatments from week 4 onward.
tained for both groups compared with baseline at
Tolerability—Tables 3 and 4 summarize the toler-
the end of the 4-week no-treatment regression phase ability assessments of both treatment formulations.
(P.05). Some differences between treatment A Treatment B produced a statistically significant
and treatment B were noted at week 2. Treatment B increase in investigator-assessed erythema compared
showed statistically significant improvement in skin with baseline at week 2 (P.042) that was not
brightness (P.05). Treatment B also showed a sta- seen in treatment A. Compared with baseline,
tistically significant reduction in the appearance of a statistically significant increase in dryness and
pores at week 2 when evaluated by the investigator peeling was noted in both treatment A and
(P.05), while treatment A did not reach statisti- treatment B as expected during the early phases
cal significance. Parity between the 2 treatments of retinization (dryness: week 2, P.004 and
was established from week 4 onward compared P.001, respectively; peeling: week 2, P.001 and
with baseline.P.002, respectively; week 4, P.039 and P.013,
Mean scores of facial lesion counts are summa- respectively). By week 12, increase in dryness
rized in Table 2. Both treatment regimens produced and peeling had resolved when assessed by the
VOLUME 89, JUNE 2012 289
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Therapeutics for the Clinician
Table 2. Mean Scores on Facial Lesion CountsaParameter
Week 2 Week 4 Week 8 Week 12 Week 16
Inflammatory lesions
aTreatment A consisted of benzoyl peroxide 5.5% with lipohydroxy acid applied twice daily and tretinoin cream 0.025% applied at bedtime. Treatment B consisted of clindamycin 1%–benzoyl peroxide 5% gel applied twice daily and tretinoin cream 0.025% applied at bedtime.Do Not Copy
investigator. In addition, no increase in erythema formulations, which can be recommended by derma-
was present as the facial skin had adapted to the tologists and other healthcare providers. Many OTC
formulations exist that can be purchased through
The participant-assessed tolerability presented mass merchandisers, direct sales, and infomercial
in Table 4 showed a statistically significant increase marketing, yet few have been tested against prescrip-
with both treatment A and treatment B in sting- tion counterparts in treatments that include tretinoin
ing (both P.001), tingling (P.007 and P.001, cream 0.025%. Because dermatologists frequently
respectively), itching (P.027 and P.007, respec- combine the antibacterial benefits of BPO with the
tively), and burning (both P.001) compared with benefits of tretinoin to target noninflammatory and
baseline at week 2. The symptoms persisted at inflammatory lesions, this regimen seemed worth-
week 4, with the exception of an insignificant dif- while to study in participants with mild to moderate
ference in itching in both treatments and in tingling acne. The OTC BPO and prescription BPO formu-
for treatment A when compared with baseline. lations demonstrated parity for efficacy and toler-
Participant-assessed irritation had largely resolved ability when used in a treatment regimen containing
by week 8 in both groups.
tretinoin cream 0.025%. Both BPO products were of
The data demonstrated parity between the 2 treat- similar particle size and composition.
ments for investigator-assessed and participant-
There are several unique attributes of the
OTC BPO formulation that merit further discussion.
The BPO 5.5% formulation used in treatment A
contained other antiacne ingredients, such as sali-
The recent movement of all single-agent BPO cylic acid and lipohydroxy acid. Salicylic acid is
products from the prescription realm to the OTC an antiacne active ingredient that can be used
realm has created a need for quality OTC BPO in concentrations up to 2% according to the
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Therapeutics for the Clinician
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olerability (Investigator Assessed)
es of Objective T
VOLUME 89, JUNE 2012 291
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Therapeutics for the Clinician
consisted of clindam
applied at bedtim
Do Not Copy
ice daily and tretinoin cream
applied at bedtim
ith lipohydroxy acid applied tw
olerability (Participant Assessed)
ice daily and tretinoin cream
es of Subjective T
consisted of benzoyl peroxide 5.5%
ith baseline.
ated on a 4-point scale (0
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Therapeutics for the Clinician
US Food and Drug Administration acne monograph.1 improvement. This formulation has the additive ben-
It is a colorless, crystalline, oil-soluble, phenolic efit of lipohydroxy acid, which may provide enhanced
compound originally derived from the willow comedolytic effects over the BPO alone.
tree.10 Salicylic acid, a -hydroxy acid also known
as 2-hydroxybenzenecarboxylic acid, can penetrate REFERENCES
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